1. Field of the Invention
The present invention relates to methods for defining genomic subgroups of tumors, cancer cell lines and subject samples related to colorectal cancer (CRC). The present invention also relates to methods for assembling panels of tumors, cancer cell lines and subject samples according to genomic subgroups for use in testing the efficacy of one or more therapeutic interventions for administering to a subject.
2. Description of Related Art
Cancer is a disease of the genome characterized by substantial variability in clinical course, outcome, and therapy responsiveness. The main factor underlying this variability is the genetic heterogeneity innate to cancers. Individual tumors of the same histopathological subtype carry different aberrations in cellular DNA.
Colorectal carcinoma (CRC) is the third most common cancer and the second leading cause of cancer death in Europe and the United States, with 300,000 new cases and 200,000 deaths each year (Midgley and Kerr, 1999). It is has been established that the oncogenic transformation of colorectal epithelium to form invasive carcinomas is driven by the sequential acquisition of tumor-specific genetic aberrations and chromosomal aneuploidy (Fearon and Vogelstein, 1990; Ried et al., 1996). Generally, tumors within the same histopathological groups follow significantly different clinical courses and respond differently to therapy. The current staging of CRC is therefore inadequate for predicting the clinical course of the disease or treatment outcome.
Improvements in cancer classification are crucial for anti-cancer drug discovery. Currently, pre-clinical models are selected based on their availability, adaptability to tumor formation in mice and growth in culture and other parameters, but they do not represent the genetic heterogeneity of the parent tumor. This leads to poor response in clinical trials to agents, which have shown excellent response in pre-clinical models.
The phenotypic diversity of colorectal tumors is accompanied by a corresponding diversity in gene copy number aberration patterns. Chromosomal aberrations are detrimental events associated with a number of developmental diseases and cancer. Amplifications and deletions of chromosomal regions occurring in somatic cells are believed to be one of the main factors leading to cancer. Systematic examination of gene copy number patterns in colorectal cancer might therefore serve as a foundation for a genomics-based molecular taxonomy of colorectal cancers. Recurrent chromosomal aberration of prognostic significance can be detected individually by classical cytogenetic analysis or fluorescent in situ hybridization (FISH) (Levsky and Singer, 2003). However, FISH analysis cannot detect the entire spectrum of genetic abnormalities as it only interrogates a limited set of chromosomal loci defined by the applied probe panel. A more advantageous diagnostic tool would be based on a refined classification of the disease. It would enable rational patient selection for treatment that can ascertain the genetic status of a subject's CRC.